4 Nanostructured products: technology and future Pierfrancesco Morganti 1 Lee Yuanhong 2 G. Morganti 3 SU M M A R Y Nanostructured products: technology and future Nanotechnologies are the set of methods and techniques for processing matter on an atomic and molecular scale to create products presenting special and improved chemical-physical features as compared to conventional ones. With the current technological k n o w - h o w, it is already possible to build diff e rent types of nanostructures (DNA, proteins, cells or viruses, etc.) on special chips that can help to better understand the function performed by proteins in cells. Thanks to nanotechnology, it is now possible to modify the chemistry and the topography of the substratum of cell cultures so as to enable them to mime the extracellular matrix, in such a way that the same signals used by cells in vivo are released. With the use of other technological platforms, it is possible to obtain thin nanostructured films organized as nets, capable of providing a huge surface that is available for interaction with the skin tissue and the external environment. An example of this is the production of 240 nm chitin nanofibrils capable of accelerating in a physiological manner the reparation of damaged skin. Chitin nanofibrils can also be used as c a rriers for pharmacological or cosmetic use. KE Y W O R D S: Nanotechnologies, Chitin nanofibrils hat is W nanotechnology 1 Professor of Applied Cosmetic Dermatology, II Università di Napoli Head of R&D, Mavi Sud s.r.l., Aprilia (LT) Visiting Professor of China Medical University Shenyang Secretary general of I.S.C.D. 2 No.1 Hospital of China Medical University Shenyang (PRC) 3 Technical Director Mavi Sud s.r.l., Aprilia (LT) Nanotechnology is understood as the characterization, type, production and use of structures and systems the exact size and shape of which must be measured on a nanometric scale. 1 Nanotechnologies are the set of methods and techniques for processing matter on an atomic and molecular scale to create p roducts presenting special and improved chemical-physical features as compared to conventional ones. What size is a nanometer (nm)? A nanometer corresponds to one billionth of a meter (Figure 1). Considering that a bacterium measures 1000 nm and that the distance between two carbon atoms of an organic molecule is 0.15 nm, one can easily comprehend how difficult it must be Figure 1. The nanometric scale. for the industry to work with such scales! Nevertheless, it is common knowledge that n a n o m a t e r i a l s p resent mechanical, optical, chemical, magnetic or electric properties that are completely different from the raw material from which they are generated

5 P. Morganti, L. Yuanhong, G. Morganti ndustry, nanotechnology I and market For these reasons, the ability to handle selectively materials of nanometric size has led the industry to develop raw materials with new p roperties and significant advantages as comp a red to the m a c roscopic world. New products are being designed, or have been designed, which present such innovative feat u res, also in terms of their applications, as to have already influenced our current lifestyle. A case in point is the wireless telephone! Other examples of innovative n a n o - p roducts p resent on the market are: sunscreens, some plastic materials with higher eco-eff i c i e n c y, coating materials that are more resistant to corro s i o n, and, naturally, microchips for cell phones, etc. How large is this market? A c c o rdi ng to the US National Science Foundation, the global n a n o - p ro d u c t s m a r k e t will register a turnover of over 1,000 billion dollars a year in the next years! (Figure 2). he technological platforms T Thanks to current technological know-how, it is already possible to build different types of nanostructures (DNA, proteins, cells or viruses, etc.) on special chips that can help to better understand the function performed by proteins in cells. One need only bear in mind that histones are proteins which the DNA ribbon contained in every cell winds around (Figure 3), and that Figure 2. Nanotechnology investment forecasts. chromosomes are huge DNA molecules wound up tidily around themselves like balls of yarn (Figure 4). Since a mistake in winding can prevent, for instance, cell reproduction, the simple de-regulation of protein activity represents an essential etiological factor in the pathogenesis of many diseases. Thanks to nanotechnology, it is now possible to modify the chemistry and the topography of the substratum of cell cultures so as to enable them to mime the extracellular matrix, in such a way that the same signals used by cells in vivo are released (Figure 5). With the use of other technological platforms, it is possible to obtain thin nanostructured films organized as nets, capable of providing a huge surface that is available for interaction with the skin tissue and the external environment (Figure 6). Figure 3. Graphic representation of DNA. Figure 4. DNA ribbon wrapped around histones. 254

6 Nanostructured products: technology and future Figure 5. The cell with its antennae that send out signals indispensable to its daily life. Figure 6. Nanostructure of a chitosan film. Figure 7. Skin repair through the use of a particular gel containing chitin nanofibrils. This was achieved by MAVI with the production of 240 nm chitin nanofibrils capable of accelerating in a physiological manner the reparation of damaged skin (Figure 7). Figure 8. Chitin nanofibril, a natural product obtained from the chelae of shellfish. hitin nanofibrils C Chitin nanofibrils (Figure 8), of an average size of 240 nm, can also be used as carriers, since they can release in a controlled manner active principles for pharmacological or cosmetic use, such as lutein, for instance. Chitin is a known natural polyglucoside that is easily recognized and hydrolized by the skin s cutaneous enzymes, while lutein, a natural oxicarotenoid, is an antioxidant capable of enriching the skin s antioxidant system. If these two molecules are properly treated, the complex resulting from their bonds can surely perform an interesting protective role on the skin and mucosae. In fact, it is capable of penetrating very easily through the skin s layers, if well dosed and vehicled, without causing toxic side effects and serving, on the contrary, as an energy deposit (Figure 9). It is interesting to underscore the ease with which these chitin nanofibrils can be included both in the natural and in the artificial fibers to generate entirely innovative tissues (Figure 10). anotechnology and development N This growth will be determined by the development and type of technology capable of generating products which, being unique for their features and properties, will be able to 255

7 P. Morganti, L. Yuanhong, G. Morganti Figure 9. Transcutaneous penetration of chitin nanofibrils. Figure 10. Chitin nanofibrils for innovative tissues. energy sensors that have made it possible to create wireless sensors, which are useful in various applications, from CBRNE (the Chemical, Biological, Radiological, Nuclear and Explosives industry) to medical diagnostics. Furthermore, in the area of security, particular nano-sensors have been introduced which, inserted in particular systems of fluids, are starting to be used to protect and alert infrastructures in case of natural disasters or terrorist-related events. 6 Also crucial for our growth is the ability to capture, file and analyze a great deal of information. Thus, the development of these new systems of sensors associated with the use of state-of-thereach the global market after being developed in a laboratory. Thus, the diff e rent technologies, from electro n i c s to optics, from information technology to biological sciences, which are all geared towards the c reation of products, when nanostructured, have generated products so innovative as to be distributed at world level in very little time. Nanotechnology will therefore be able to spearhead innovation, giving new impetus to a globalized and ever faster trade! While some metals, such as Ti, Cu, Ni and Sn, have proven to be more pliable and stronger when nanostructured, many nano-assembled products have revealed exceptional efficiency features. These include many substances used in catalysis, various superconductors, batteries with a higher energy charge and longer duration, membranes with higher permeation features, as well as some biomedical structures or particular microcircuits to be used in the field of security and for brand protection. 3 nnovative nanotechnologies I Some examples of such innovative technologies are electronic nano-tubes, structures used in information technology and in many medical fields like molecular diagnostics based on nanostructured biosensors (Figure 11), or nanostructures capable of transporting drugs or active principles for cosmetic use 4, or polymers used for diagnostic or monitoring purposes, etc. 5 Nanotechnology has there f o re inspired the development of exceptionally small and low- Figure 11. EAP sensors designed with Electroactive Polymers. 256

8 Nanostructured products: technology and future Figure 12. Finland United States Sweden Denmark Taiwan Singapore Iceland Switzerland Norway Australia Netherlands Japan Great Britain Figure 13. Competitiveness classification Canada Germany Portugal Ireland Spain France Jordan Greece Botswana China India Italy art information technology will step up our ability to quickly perceive, understand and process complex messages that are hard to interpret. arketing nano-structured M products The ability to market nano-structured products will depend on the ability of companies to produce and control this new class of products, meeting the needs of both man and the environment, on the ability of governments to regulate their production and use quickly and effectively, and on the ability of the products themselves to meet the needs and expectations of consumers. That is why it is necessary for all these nanoproducts to be designed and sold in a way that fully respects the health of consumers and the environment; in other words, they must be bio and ecocompatible. In order to reach these objectives, industries must create new plants, investing the necessary capital, while governments must support adequately and with rapid decisions these industrial efforts also by introducing new services. On the other hand, both industries and the Italian government should significantly increase investments in research and development to keep pace with more virtuous European countries and with the US (Figure 12). In fact, Italy must be more competitive at the international level to maintain the level of wellbeing reached by its citizens (Figure 13). isks/benefits of nanoproducts R Any production process that generates profit inevitably entails risks and benefits. Naturally, this also applies to all nanostructured processes. When assessing the risks/benefits of these new chemical structures, the products must be distinguished according to two main categories: nanoderivatives present in nature and manmade ones. It is therefore necessary to determine whether they can be absorbed through the skin or mucosae, controlling their possible topical and/or systemic toxicity; needless to say, this should be done after studying their physicalchemical properties, such as for instance: (a) the state of distribution of the single nanoparticles; (b) the state of agglomeration and size of their crystal structure; (c) the composition and chemical features of the developed surface; (d) the electrical charges present in their structure; and (e) their possible porosity. Synthetic nanostructures include, for instance, fullerene which, depending on whether or not it includes OH groups in its structure, displays completely different chemical/physical properties and behaviours, also developing a different tendency for transcutaneous penetration. Another example of a product created in the lab is the carbon nanotube which is also used in the biomedical field. 257

9 P. Morganti, L. Yuanhong, G. Morganti Figure 14. Skin penetration as a target for studying the possible toxicity of active principles. Figure 15. Penetration of nanotubes through the skin layers. Detail. These, like other synthetic nanostructures, penetrate inter- or intracutaneously in the conventional way (Figure 14). Trials showed that nanotubes can be inserted in the keratinocytes at different levels, remaining intact within biological structures (Figures 15 and 16). A completely different behaviour was observed in natural nanostructures like chitin nanofibril 7,8 (Figure 17), which, like polyglucoside, is rapidly catabolized and reduced to glucose and glucosamine by the enzymes of the skin or of the mucosae following the normal catabolic process 9 (Figure 18). In fact, these nanofibrils, on which chemicalphysical as well as biological studies have already been conducted, appear to be useful as active carriers to be employed in cosmetics as well as in the area of smart bio tissues. 10 Naturally, in order to be applied to the skin for pharmaceutical or cosmetic purposes, all these nanostructures must be introduced in suitable vehicles capable of transporting them through the cell layers by means of penetration. It is therefore possible to create macro, micro or nanoemulsions made up of different sized particles, the shape and size of which must be known (Figure 19). Figure 16. Penetration of nanotubes through the skin layers. Detail. Chitina Sol. Fisiologica Figure 17. Chitin nanofribril. Figure 18. The cell activity carried out by chitin nano fibtrils corresponds perfectly with the activity carried out by a normal vehicle. 258

10 Nanostructured products: technology and future Figure 19. Naturally, it is necessary to prove by means of trials the types and features of the emulsion considered and the size of the particles obtained (Figures 20 and 21) following the model, for instance, of NANOCREAM by Sinerga. 11 In any event, it is important to underscore that nanotechnologies can surely offer new benefits to society, be a source of new progress and create new jobs, thus improving also the quality of our life. However, it is necessary for research to dedicate more resources to assess their safety and determine the impact that nanomaterials will have on the environment and on health. Therefore, it is important that EU Member States focus their resources on developing the methodologies to be followed, while industries monitor their products and pro d u c t i o n methodologies, verifying the impact they have on human health and the environment. To this end, European chemical industries have actively participated in and supported specific national and international projects involving n a n o p roducts (N a n o c a re: info and NanoSafe2: www. n a n o s a f e. o rg) to verify their potential effects on man and the enviro n- m e n t. 1 2 There are many challenges to be overcome in the initiatives against and in the ones in favour of the more or less rapid distribution of nanoproducts (Figure 22). Figure 20. Characterization of the micelles of a SINERGA nanocream (Nanocream). Figure 21. Characterization of the micelles of a SINERGA nanocream (Nanocream). C onclusions In order to market nanostructure d p roducts and develop the related pro d u c t i o n p rocesses, in the short term both the industry and governments shall have to invest on building new infrastructure and utilize venture capital. On the other hand, the implementation and long-term success of nanotechnologies shall depend on a rational, informed and transp a rent dialogue among all the parties involved, which shall have to try to understand both the potential for developing a green and sustainable chemistry and the potential negative e ffects on human health and the enviro n m e n t that may arise. Side effects must be reduced and aspects that may help to improve the effectiveness of the p roducts must be enhanced as much as possible. The constant and factual collaboration of governments, universities and industries will lead to organizing new technological platforms and new products capable of enhancing the quality of life of individuals and of society as a whole. This project is part of the 7 t h E u ro p e a n Framework Programme (FP7) in which platform 259

12 308 nm monochromatic excimer light in the treatment of psoriasis Steven P. Nisticò Rosita Saraceno Catia Schipani Antonio Costanzo Sergio Chimenti SU M M A R Y 308 nm monochromatic excimer light in the treatment of psoriasis B a c k g round: Various reports showed the efficacy of Narrow Band UVB ( nm) and excimer laser (308 nm) in the treatment of psoriasis. Objective: To prove the efficacy of light produced by xenon-cloride excimer at 308 nm (Monochromatic Excimer Light, MEL) in the treatment of stable forms of localized plaque psoriasis. Patients and methods: This study was an open trial with 152 patients affected with stable mild to moderate plaque psoriasis (PASI score between 4 and 12) were t reated with a weekly session of MEL A total number of 6-16 sessions was p e rformed with a dose increase according to patient phototype and re s p o n s e. Results: 152 patients were enrolled in the study and 149 completed the pro t o c o l. Patients were followed up every two weeks, 57 patients for one-year and 92 patients for 6 months. After 4 months there was complete remission in 87 patients, partial remission in 37 and moderate improvement in 25 patients. Conclusions: These pre l i m i n a ry results suggest that MEL can be considered as a valid option for treatment of selected forms of localized plaque psoriasis. KE Y W O R D S: Psoriasis, MEL, 308 nm Department of Internal Medicine Chair of Dermatology Policlinico Tor Vergata University of Rome, Tor Vergata, Italy I ntroduction Psoriasis is a distressing, chronic skin disease characterised by keratinocyte hyperproliferation with the presence of acute and chronic inflammatory cells. Treatment for psoriasis include topical corticosteroids, tar, anthralin, vitamin D analogues, tazarotene and salicylic acid. 1 UVB phototherapy and PUVA photochemotherapy are also effective and well documented therapeutic options for psoriasis. In particular Narrow Band phototherapy involves irradiation on the UVB spectrum at a wavelength between 300 and 313 nm. In this spectrum, the UVB activity is effective and safe, and offers long term remission. Use of 308 nm excimer laser for psoriasis has been reported since Furthermore the efficacy of the light produced by xenon-cloride excimers at 308 nm has been reported by several authors 3-10 in the treatment of stable forms of localized plaque psoriasis with a satisfactory benefit/risk profile. Some investigators showed that repeated treatments may achieve a prolonged and stable relapse free disease, 7 through a modulation of the local immune response 6, T cell depletion and alterations in apoptosis related molecules. 11 To confirm a previous study we performed an open trial in 152 patients affected by localized psoriasis. aterials and methods M The excimer is an excited dimer, a molecule formed by the combination of two atoms, a noble gas Xenon and Cloride. The excitation of the molecule emits an ultraviolet photon at 308 nm. The excimer light (MEL, Excilite TM Deka Medical Lasers, Florence, Italy) is a monochromatic non coherent laser; it releases a power density of 48 Mw/cm 2 at the distance of 15 cm 263

13 S.P. Nisticò, R. Saraceno, C. Schipani, A. Costanzo, S. Chimenti from the source and it has an irradiation area of 512 cm 2. In this study, conducted in the Dermatology Department of University of Rome Tor Vergata, were recruited 152 patients of Fitzpatrick skin type 2-3 (80 men and 72 women) with stable mild to moderate plaque psoriasis, age range (mean age of 48) years. All patients signed informed consent to therapy, and were instructed to avoid any topical or systemis medication for psoriasis during the treatment period. Stable plaques were defined as those that had been present and unchanged for a minimum of 2 months. Disease duration was 1-30 years. Patients were affected from localized plaque psoriasis (Table 1) with an involvement of < 15% of the body surface, with a PASI score from 4 to 12. All patients gave informed consent, and were instructed to avoid session of any topical medication during MEL treatment. Patients with a history of skin cancers or photosensitivity related disorders were excluded. Patients who had been on systemic medication for less than 8 weeks, phototherapy for 4 weeks or had used topical treatments within the past 2 weeks were also excluded. Photographs were taken at baseline, on clearing if clearing occurred, and after 4 months of treatment. Minimal Erythemal Dose (MED) was determined before treatment on healthy and unexposed skin on the dorsal area of the arms. MED was evaluated at increasing light dosage. The following doses were obtained (Tables 1, 2). The initial dose of MEL was calculated according to patient phototype, thickness of the squamous component of the psoriatic plaque and the anatomical area. A double MED dose was used for the lesions on the dorsal and posterior arms and a threefold to fourfold MED dose for more infiltrated lesions with a thicker squamous component localized in more photoresistant cutaneous regions such as elbows, knees, dorsal hands and palmo-plantar areas. Single plaques were irradiated protecting the surrounding non affected skin and petrolatum ointment was applied on the scaly patches to minimize light reflection prior to irradiation. Treatment was reported every 7 days with a dose increase of mj/cm 2 at each session according to patient phototype and response to previous session as observed with the flattening of the plaques and their reduction in size, erythema, scaling and pustules. Clinical examination was evaluated before every session and the PASI score 7 calculated every 2 weeks. A maximum of 16 sessions was performed and usually phototherapy was discontinued when all lesions had completely cleared. Response rate was defined as complete (an improvement in the PASI score between 75 to 100%), partial (50 to 75%) and slight (25 to 50%). R esults In our study 152 patients were enrolled and 149 patients completed treatment with 6-16 (mean 11) weekly sessions; 57 patients had one year and 92 patients 6 months of follow up. After 4 sessions of MEL all patients showed a PASI improvement. In those patients who had a complete remission we carried out a maintenance session of 2 J/cm 2 every 14 days until we reached a 120day follow-up. Table 1. Phototype % patients Complete remission 58% Partial remission 25% Moderate improvement 17% Table 3. Clinical results. MED I 4 sec 200 m J/ cm 2 II 5 sec 250 m J/ cm 2 III 4 sec m J/ cm 2 IV 7-8 sec m J/ cm 2 MED: Minimal Erythematous Dose Table 2. MED at 308 nm. Site Number Number Mean Cumulative of patients of session UV dose (%) (mean) (J/cm 2 ) Knees 55% Elbows 58% Legs 17% Palmoplantar areas 45%

14 308nm monochromatic excimer light in the treatment of psoriasis BEFORE AFTER Figure 1a and b. Localized psoriasis before and after MEL 1a 1b Figure 2a and b. Palmar psoriasis before and after MEL 2a 2b Figure 3a and b. Plantar psoriasis before and after MEL 3a 3b After 4 months 87 patients (58%) showed a complete remission, 37 patients (25%) had partial remission and 25 patients (17%) only moderate improvement. (Table 3). A 75% improvement in the PASI score (PASI 75) was considered as the primary efficacy endpoint. This result was achieved in 98 patients after the fourth session, at week 4 and in 130 at week 8. This benefit was mantained at a 16-week follow-up in 125 patients, whereas all the patients that completed treatment maintained the achieved result. A prolonged erythema (24-48h) was observed in 52 patients after the first and second session with a mild pruritic sensation in 39. These common side effects were well tolerated. Transient hyperpigmentation in the tre a t e d areas was noticed in 3 patients; this effect resolved spontaneously 2 weeks after the end of treatment. Formation of vesicles and oedema were observed in 1 patient after 3 treatments, which resolved following topical application of hydrocortisone 1% ointment for 3 days. However, the patients responded to the following sessions and completed successfully the treatment 265

15 S.P. Nisticò, R. Saraceno, C. Schipani, A. Costanzo, S. Chimenti D iscussion 308-nm excimer light and laser treatments appear to offer relapse-free periods and a prolonged stabilization of localized psoriasis. Bonis et al. 2 and other authors 3-5 showed that 308 nm excimer light and laser therapy appear to be safe and effective for localized plaque psoriasis, comparable or better than that offered by standard topical therapy regimes and by 311nm UVB treatment. Feldman et al. 6 in 2002 reported results of a multicenter study in 80 patients which showed that monochromatic 308-nm excimer laser has been effective and safe for psoriasis. Cappugi et al. 7 and Campolmi et al. 8 in recent reports showed an improvement ranging from 75% to 100% with MEL in patients with palmoplantar psoriasis with no relapse in an over 16- week follow-up. G u p t a S A et al. 9 in 2002 and Gupta SN et al. 10 i n 2004 showed M.E.L to be safe and effective in t reating patients with recalcitrant scalp psoriasis. Cappugi suggested that 308 nm MEL (Excilite) plays an essential role in dramatically decreasing cytokine expression in psoriatic skin accompanied by clinical remission. In addition, Bianchi et al. 11 confirmed the efficacy of MEL in 2003 showing that light therapy with monochromatic excimer laser on psoriatic skin is associated with significant T cell depletion and alterations in apoptosis-related molecules, accompanied by a decreased proliferation index and clinical remission. In our opinion, further data are re q u i red to determine how the MEL remission rate can be maximized in order to provide patients with a good long-term control of their disease. In this study we demonstrated the benefits of MEL such as the selective use of high doses with a partial or total remission in over 50% of the patients. Furthermore we showed a reduction of the number of sessions and few patient visits vs N a r row Band UVB and traditional phototherapy. We also showed that dose variation represents the most important feature in the variability of clinical responses. The results we obtained were encouraging although the costs and the small number of centres, which can provide this treatment modality, are a limiting factor. More studies will be necessary to evaluate different therapeutical schemes and to evaluate any long-term side effects. In conclusion, this preliminary study proposes the use of MEL as a valid choice in the treatment of selected variants of psoriasis with a good overall efficacy even in the absence of topical/systemic drugs as well as the efficacy of combined therapies. R eferences 1. Lebwol M. Psoriasis. Lancet 2003; 361: Bonis B, Kemeny L, Dobazy A, et al. 308 nm UVB excimer laser for psoriasis. Lancet 1997; 350(9090): Asawanonda P, Anderson RR et al. 308 nm excimer laser for treatment of psoriasis: a dose-response study. Arch. Dermatol 2000; 136: Trehan M, Taylor CR. High-dose 308 nm excimer laser for the treatment of psoriasis. J Am Acad Dermatol 2002; 46: Feldman SR. Remissions of psoriasis with excimer laser treatment. Dermatology Online Journal 2002; 8:23 6. Feldman SR, Housman TS, Fitzpatrick RE et al. Efficacy of the 308-nm excimer laser for treatment of psoriasis: results of a multicenter study. J Am Acad Dermatol. 2002; 46: Cappugi P et al. 308 nm monochromatic excimer light in psoriasis. Clinical evaluation and study of cytokine levels in the skin. Int. J. Immunopath and Pharmacol. 2002; 1 3 : Campolmi P. et al. 308 nm monochromatic escimer light for the treatment of palmoplantar psoriasis. Int. J. Immunopath and Pharmacol. 2002; 13: Gupta, SA, Taneia A; Trehan, MA; Taylor, CR. A 308 nm excimer laser for the treatment of scalp psoriasis. Photodermatology, 2002; 18: Gupta SN, Taylor CR. 308-nm Excimer Laser for the t reatment of scalp psoriasis. Arch Dermatol 2004; 140: Bianchi B et al. Monochromatic axcimer light (308 nm): an immunohistochemical study of cutaneous T cells and a p o p t o s i s - related molecules in psoriasis. JEADV 2003; 17:

16 Superficial chemical peeling with a lipophilic derivative salicylic acid in chrono and photoaging Gabriella Calabrò Emanuela Fiammenghi Viviana Lo Conte Serena La Bella Fabio Ayala SU M M A R Y Superficial chemical peeling with a lipophilic derivative salicylic acid in chrono and photoaging Chronoaging, photoaging and mechanical stress induce profound alterations of skin structure. The intrinsic aging also known as chronological aging is due to genetic factors and metabolic processes, including hormonal alteration that induce dermal and hypodermal atrophy in elderly. Extrinsic aging or environmental aging is prevalently promoted by sun exposure. Therefore the improvement of fine lines, wrinkles and hyperpigmentation marks is one of the most important field of interest of dermocosmetology. Since several years chemical peelings are used to improve the appearance of damaged skin. In this study was evaluated the effectiveness of a salicylic acid derivative known as!-lipohydroxy acid (LHA TM, BIOMEDIC LHA-PEEL ) on the face of marked signs of aging. Were enrolled 20 volunteers women aged between 45 and 65 years; 5% LHATM was applied once weekly for two weeks and 10% LHATM was used once every 14 days for three steps. To evalue the efficacy of the peeling were carry out clinical examination, photographic study and cutaneous non invasive evaluations, such as colorimetry (Spectrocolorimeter X-Rite ) and corneometry (Corneometer CM 820 ). The results have showed a significant increase of skin hydration middle and an improvement in complexion clearness. The volunteers experienced cosmetic benefits in the clinical parameters like reported by a self-evaluation questionnaire. Therefore, the lipophilic derivative salicylic acid has showed an elevated tolerance without minimal adverse erythematous events. KEY WORDS: Peeling,!-lipohydroxy acid (LHA), Chronoaging, Photoaging, Complexion clearness Section of Clinical Dermatology Department of Systematic Pathology University Federico II of Naples I ntroduction Human skin, like all other org a n s, u n d e rgoes chronological aging. In addition, unlike other organs, skin is in direct contact with the environment and there f o re undergoes aging as a consequence of environmental damage. 1 C h ronoaging, photoaging and mechanical stress contribute to modify deeply the structure of the skin altering its colour and texture. The mechanisms of skin ageing involve intrinsic and extrinsic factors. 2, 3 Intrinsic factors are hereditary, and comprise the skin phototype, which is responsible for natural photoprotection, and the bone structure, which plays a role in tissue resistance and the distribution of facial fat. 2 The skin is an organ that is affected by hormones, especially oestrogens, androgens and progesterone. Modification of the hormonal balance at the menopause also plays a role in skin 271

17 G. Calabrò, E. Fiammenghi, V. Lo Conte, S. La Bella, F. Ayala ageing like a progressive atrophy of derma of ipoderma and of the structures of support. 3 Extrinsic factors are mainly UV radiation, which is a major cause of skin ageing 4 and also of actinic keratoses, skin carcinomas and melanomas. The primary environmental factor that causes human skin aging is UV irradiation from the sun. This sun-induced skin aging (photoaging), like chronological aging, is a cumulative process. However, unlike chronological aging, which depends on the passage of time per se, photoaging depends primarily on the degree of sun exposure and skin pigment. 5 Therefore, the most appropriate treatments may then be offered to the patient. This comprehensive approach to care requires knowledge of the mechanisms of skin ageing and the advantages and drawbacks of the different therapeutic approaches available, in order to arrive at the best therapeutic strategy and to meet patient expectations. The use of chemical peeling agent, laser resurfacing or topical retinoids can reverse same of the signs of photoaging. Chemical peeling continues to be the gold standard in cosmetic 2, 6, 7, 8 enhancement of facial skin. The word p e e l s covers several kinds of treatment that, by application of a chemical agent, causes destruction of a part of entire epidermidis, with or without the dermis, leading to exfoliation and removal of superficial lesions, followed by regeneration of new epidermal and dermal tissue. These are classified as superficial, medium-depth or deep peels. 9 The level of penetration, destruction and inflammations determines the level of peeling. All types of peels may produce mild irritation or predispose to herpes infection. The agents most often used for superficial peels are the alphahydroxy acids, such as glycolic, lactic, malic, tartaric, citric and salicylic acids. They are widely used of their exfoliating and rejuvenating effect on photo-aged skin. Although the literature is replete with the use of alphahydroxy acids, there is dearth of published data regarding the efficacy and safety of salicylic used. 10 Salicylic acid is an excellent keratolitic agent because of its exfoliating and rejuvenating effect on photoaged skin. It is though to function through solubilisation of intercellular cement, thereby reducing corneocyte adhesion. It is a beta-hydroxy acid, an hydroxyl derivative of benzoic acid and represent a carboxylic acid attached to an aromatic alcohol, phenol. Recently, a lipophilic derivative of salicylic acid known in the literature as 2-hydroxy-5-octa- noyl benzoic acid or!-lipohydroxy acid (!- LHA) (Figure 1), has been tested as a superficial peel at concentrations of 5% to 10% LHA TM. 11 Developed by an advanced re s e a rch team, the L H A T M molecule (lipo-hydroxy-acid) is a lipophilic derivative of salicylic acid that incorporates a fatty chain for improved affinity with the epidermis allowing for faster skin re g e n e r a t i o n. The aim of the study has been to evaluate the cosmetic efficacy on ageing skin (chrono- and photo-damaged) of!-lha, a new superficial peeling. aterial and Methods M A total of 20 volunteers women aged between 45 to 65 years who attended our dermatological clinic in Naples with marked signs of chrono and photoaging including presence, on the face, of fine lines and wrinkles, dry skin and mottled pigmentation, constituted the subjects for this study. Before starting therapy, for all patients, anamnesis was carried out and the following factors evaluated: age, sex, eventual pathologies and therapies in progress, photoageing and chronoaging status and skin typing according to Fitzpatrick s classification. Pregnant and lactating ladies, patients having known sensitivity to acetylsalicylic acid and other salicylates (like aspirin), wounds skin and impracticable photoprotection, and those with a known keloidal tendency or having active or past herpes simplex infection, were excluded. The volunteers applied a solution containing 5 and 10 % salicylic acid derivative,!-lipohydroxy acid (LHA TM, BIOMEDIC LHA-PEEL ) (Figure 1) to the face. The face is previously degreased by scrubbing with a cotton gauze piece soaked with a solution with absolute ethanol and acetone (50%/50% v/v). Figure 1. Chemical structure of!-lipohydroxy acid (!-LHA). 272

18 Superficial chemical peeling with a lipophilic derivative salicylic acid in chrono and photoaging Five peeling sessions were carried put in each patients: the product containing 5% LHA TM was applied once weekly at first and second session, whereas in the remaining sessions 10% LHA TM was used once every 14 days. Two layers of application were employed in first and second session, but three layers or four, if it was necessary, were applied during the remains weeks. No neutralization was required and also moisturizing creams were applied after the application of chemical peel. We always prescribed a high SPF level sunscreen (50 + ) product with UVA/UVB protection to be applied immediately after the procedure and on a daily basis over the following 2 weeks. To value the efficacy of the peeling were carry out clinical examination, photographic study using standard positioning, and cutaneous noninvasive evaluations, such as colorimetry (Spectrocolorimeter X-Rite ) and corneometry (Corneometer CM 820 ), at week 0 (baseline) and week 8 (completion of study). Tolerance to the procedure and any undesirable effects noted during sessions were recorded. Finally, a selfevaluation questionnaire was administered to all patients. R esults All the 20 patients included in the trial, completed the study. Sixteen patients (80%) had skin of Fitzpatrick phototype III and the re m a i- ning four (20%) phototype II (Figure 2). We have obtained in all patients a significant increase of skin hydration (middle 53%) measured using Corneometer CM 820 (Figure 3). The clarifying power of the LHA was confirmed by an increase in average of 2 in the luminosity index (L*) with the spectrocolorimeter (X-Rite 968) (Figure 4); this results was more evident for patients with skin phototype III. At the end of the treatment the dermatologists indicated the % ameliorations for a number of cosmetic parameters (Figure 5). The dermatologists considered that the main improvement was in decreasing order: clearness complexion (100%), wrinkles (70%), smooth- Figure 2. Distribution of skin types. Figure 3. Values of skin hydration in our 20 patients at the beginning (T0) and at the end (T1) of the treatment and average of the increase expressed in arbitrary units. Figure 4. Values of clearness complex in our 20 patients at the beginning (T0) and at the end (T1) of the treatment and average of the luminosity index (L*) increase. Figure 5. % improvement of the skin for a number of cosmetic parameters examined before and after the treatment by the dermatologists. 273

19 G. Calabrò, E. Fiammenghi, V. Lo Conte, S. La Bella, F. Ayala ness (58%) and firmness (20%). They didn t observed any effect on fine lines, confirming the instrumental results. F rom data reported by the self-evaluation questionnaire, it was valued the % ameliorations assessed by the volunteers for a number of cosmetic parameters (Figure 6). The patients found that clearness complexion was mostly i m p roved (100%), followed by smoothness (66%), healthy complexion (58,3%), softness (50%), than firmness (33%). The procedure was very tolerated by almost all the patients (Figg. 7-10). Only two patient (10%) experienced mild burning and irritation immediately after application of the peeling agents that lasted for a few minutes and gradually settled down within half an hour. Figure 6. % improvement of the skin after the treatment assessed by the panellists. Figure 7. Fifty-one years old patient: before (a 1, b 1 ) and after (a 2, b 2 ) LHA peeling treatment. Figure 8. Sixty-four years old patient, before (a) and after (b) LHA peeling treatment. 274

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